The present invention relates to novel, rapidly curing adhesives based on hydrophilic polyisocyanate prepolymers for use in surgery.
In recent years, increasing interest has developed in the replacement or complementation of surgical sutures through the use of suitable adhesives. Particularly in the field of plastic surgery, in which particular value is placed on thin, as far as possible invisible scars, adhesives are being increasingly used.
Tissue adhesives must have a number of properties in order to be accepted among surgeons as a substitute for sutures. These include ease of use and an initial viscosity such that the adhesive cannot penetrate into deeper tissue layers or run off. In classical surgery, rapid curing is required, whereas in plastic surgery correction of the adhesive suture should be possible and thus the curing rate should not be too rapid (ca. 5 mins). The adhesive layer should be a flexible, transparent film, which is not degraded in a time period of less than three weeks. The adhesive must be biocompatible and must not display histotoxicity, nor thrombogenicity or potential allergenicity.
Various materials which are used as tissue adhesives are commercially available. These include the cyanoacrylates Dermabond® (octyl 2-cyanoacrylate) and Histoacryl Blue® (butyl cyanoacrylate). However, the rapid curing time and the brittleness of the adhesion site limit their use. Owing to their poor biodegradability, cyanoacrylates are only suitable for external surgical sutures.
As alternatives to the cyanoacrylates, biological adhesives such as peptide-based substances (BioGlue®) or fibrin adhesives (Tissucol) are available. Apart from their high cost, fibrin adhesives are characterized by relatively weak adhesive strength and rapid degradation, so that this is only usable for smaller incisions in untensioned skin.
Isocyanates-containing adhesives are all based on an aromatic diisocyanate and a hydrophilic polyol, the isocyanates TDI and MDI preferably being used (US 20030135238, US 20050129733). Both can bear electron-withdrawing substituents in order to increase their reactivity (WO-A 03/9323).
Difficulties until now were the low mechanical strength (U.S. Pat. No. 5,156,613), excessively slow curing rate (U.S. Pat. No. 4,806,614), excessively rapid biodegradability (U.S. Pat. No. 6,123,667) and uncontrolled swelling (U.S. Pat. No. 6,265,016).
According to US patent 20030135238, only polyurethane prepolymers with a trifunctional or branched structure which are also capable of forming hydrogels are suitable adhesives. The adhesive must also be capable of forming a covalent bond to the tissue. US 20030135238 and US 20050129733 describe the synthesis of trifunctional, ethylene oxide-rich TDI- and IPDI-(US 20030135238) based prepolymers which react with water or with tissue fluids to give the hydrogel. Sufficiently rapid curing was until now only attained with the use of aromatic isocyanates, which however react with the formation of foam. This results in penetration of the adhesive into the wound and hence in the wound edges being pushed part, which results in poorer healing with increased scarring. In addition, the mechanical strength and the adhesion of the adhesive layer is decreased by the foam formation. In addition, on account of the higher reactivity of the prepolymers, reaction of the isocyanate radicals with the tissue takes place, as a result of which denaturation, recognizable through white coloration of the tissue, often occurs.
As a replacement for the aromatic isocyanates, lysine diisocyanate has been studied, but owing to its low reactivity this reacts only slowly or not at all with tissue (US 20030135238).
In order to increase their reactivity, aliphatic isocyanates have been fluorinated (U.S. Pat. No. 5,173,301), however this resulted in spontaneous autopolymerization of the isocyanate.
EP-A 0 482 467 describes the synthesis of a surgical adhesive based on an aliphatic isocyanate (preferably HDI) and a polyethylene glycol (Carbowax 400). Curing takes place on addition of 80-100% water and a metal carboxylate (potassium octanoate) as catalyst, during which a foam is formed, which is stabilized with silicone oil.
Systems based on aliphatic isocyanates display only insufficient reactivity and hence an excessively slow curing time. Although the reaction rate could be increased by the use of metal catalysts, as described in EP-A 0 482 467, this resulted in the formation of a foam, with the problems described above.
The fundamental suitability of aspartate esters for the crosslinking of prepolymers is well known in the state of the art in the context of surface coatings and is for example described in EP-A 1 081 171 or DE-A 102 46 708.